Functional analysis of a set of genes related to the molecular targeted therapy resistance in glioblastoma and the development of novel therapeutic strategies

• Project/Area Number: 23390343
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: The University of Tokyo
• Principal Investigator: MUKASA Akitake 東京大学, 医学部附属病院, 講師 (90463869)
• Co-Investigator(Kenkyū-buntansha): SAITO Kuniaki 杏林大学, 医学部, 助教 (50446564) ; TANAKA Minoru 東京大学, 医学部付属病院, 助教 (50332581)
• Research Collaborator: OHTANI Rhyohei ; OMATA Mayu
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2012: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 膠芽腫 / 分子標的治療 / 治療耐性 / EGFR / 腫瘍幹細胞 / 脳腫瘍幹細胞 / 分子標的療法

Outline of Final Research Achievements

Molecular targeted therapy against epidermal growth factor receptor (EGFR）had been tested for malignant gliomas (glioblastomas), however, the efficacy was limited since the tumors rapidly became resistant to the targeted therapy. In this study, we analyzed the function of a set of resistance-related genes that we identified in the previous study and called “SDeltaE” (the substitute for Delta EGFR expression). Some of candidate SDletaE genes were revealed to be upregulated in glioma-initiating cells. Inhibition of these SDeltaE led to suppression of tumor cell growth and invasion. Hence, these genes were expected be the novel targets in malignant gliomas.

Research Products

• [Journal Article] H3F3A K27M mutations in thalamic gliomas from young adult patients (2014)
  • Author(s): Aihara K, Mukasa A, Gotoh K, Saito K, Nagae G, Tsuji S, Tatsuno K, Yamamoto S, Takayanagi S, Narita Y, Shibui S, Aburatani H, Saito N
  • Journal Title: Neuro Oncol Volume: 16 Issue: 1 Pages: 140-146
  • DOI: 10.1093/neuonc/not144
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma (2014)
  • Author(s): Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana, Jalbert, Nelson, Bollen, Gustafson, Charron, Weiss, Smirnov, Song, Olshen, Cha, Zhao, Moore, Mungall, Jones SJ, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger S, Chang SM, Taylor BS, Costello JF
  • Journal Title: Science Volume: 343 Issue: 6167 Pages: 189-193
  • DOI: 10.1126/science.1239947
  • Peer Reviewed / Open Access
• [Journal Article] PCDH10 is required for the tumorigenicity of glioblastoma cells (2014)
  • Author(s): Kanae Echizen, Mitsutoshi Nakada , Tomoatsu Hayashi, Hemragul Sabit, Takuya Furuta, Miyuki Nakai, Ryo Koyama-Nasu, Yukiko Nishimura, Kenzui Taniue, Yasuyuki Morishita, Shinji Hirano, Kenta Terai, Tomoki Todo, Yasushi Ino, Akitake Mukasa, Shunsaku Takayanagi, Ryohei Ohtani, Nobuhito Saito, Tetsu Akiyama
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 444 Issue: 1 Pages: 13
  • DOI: 10.1016/j.bbrc.2013.12.138
  • Peer Reviewed / Open Access
• [Journal Article] 成人神経膠腫の分子生物学 (2014)
  • Author(s): 武笠 晃丈
  • Journal Title: 脳21 Volume: 17 Pages: 49-56
• [Journal Article] Significance of IDH mutation varies with tumor histology,grade, and genetics in Japanese glioma patients. (2012)
  • Author(s): 武笠晃丈、高柳俊作、齊藤邦昭、柴原純二、田部井勇助、成田善孝、西川亮、植木敬介、斉藤延人.
  • Journal Title: Cancer Science Volume: 103(3) Issue: 3 Pages: 587-92
  • DOI: 10.1111/j.1349-7006.2011.02175.x
  • Peer Reviewed
• [Journal Article] Spontaneous regression of germinoma in the pineal region before endoscopic surgery: A pitfall of modern strategy for pineal germ cell tumors (2011)
  • Author(s): Ono H
  • Journal Title: J Neurooncol Volume: 103 Issue: 3 Pages: 755
  • DOI: 10.1007/s11060-010-0432-1
  • Peer Reviewed
• [Journal Article] Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells (2011)
  • Author(s): Watanabe, A., et al
  • Journal Title: Proceedings of National Academy of Science U.S.A. Volume: 108 Issue: 30 Pages: 12384
  • DOI: 10.1073/pnas.0906930108
  • Peer Reviewed
• [Journal Article] Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma (2011)
  • Author(s): Li M
  • Journal Title: J Exp Med Volume: 208 Issue: 13 Pages: 2657-73
  • DOI: 10.1084/jem.20111102
  • Peer Reviewed
• [Journal Article] がんゲノムアトラスと脳腫瘍 (2011)
  • Author(s): 武笠晃丈
  • Journal Title: 脳神経外科速報 Volume: 21 Pages: 654-661
• [Journal Article] 悪性グリオーマにおけるIDH遺伝子変異 (2011)
  • Author(s): 武笠晃丈
  • Journal Title: 癌と化学療法 Volume: 38 Pages: 937-40
• [Presentation] 神経膠腫の悪性化に伴うジェネティック・エピジェネティックな進化 (2013)
  • Author(s): 6.武笠晃丈、齊藤邦昭、相原光輝、Brett E. Johnson、高柳俊作、大谷亮平、田中將太、上田 宏生、山本 尚吾、辰野 健二、永江玄太、島村徹平、成田善孝、永根基雄、西川亮、植木敬介、宮野悟、Joseph F. Costello、油谷浩幸、斉藤延人
  • Organizer: 第31回日本脳腫瘍学会
  • Place of Presentation: 宮崎
  • Year and Date: 2013-12-08 – 2013-12-10
• [Presentation] Tumor suppressive role of DACH1 in glioblastoma stem-like cell (2013)
  • Author(s): 5.Akitake Mukasa, Akira Watanabe, Hideki Ogiwara, Nobuhito Saito, Hiroyuki Aburatani
  • Organizer: The 4th Quadrennial Meeting of the World Federation of Neuro-Oncology (WFNO)/ the 18th Annual Society for Neuro-Oncology (SNO) Meeting
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2013-11-22 – 2013-11-25
• [Presentation] 神経膠腫の悪性化に伴うジェネティック・エピジェネティックな変化 (2013)
  • Author(s): 4.武笠晃丈、齊藤邦昭、相原功輝、高柳俊作、大谷亮平、田中將太、上田 宏生、山本 尚吾、辰野 健二、永江玄太、島村徹平 Teppei Shimamura、成田善孝、永根基雄、西川亮、植木敬介、宮野悟、油谷浩幸、斉藤延人
  • Organizer: 第71回日本脳神経外科学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-16 – 2013-10-18
• [Presentation] The Epigenetic Profiling of Malignant Gliomas (2013)
  • Author(s): Akitake Mukasa
  • Organizer: The XV WFNS World Congress of Neurosurgery
  • Place of Presentation: Seoul (Korea)
  • Year and Date: 2013-09-08 – 2013-09-13
  • Invited
• [Presentation] The Identification of Therapeutic Targets for Glioma through Genetic and Epigenetic Profiling (2013)
  • Author(s): Akitake Mukasa
  • Organizer: The 23rd Annual Meeting of the Korean Brain Tumor Society
  • Place of Presentation: Daegu (Korea)
  • Year and Date: 2013-06-29
  • Invited
• [Presentation] Genetic and Molecular Profiling of Malignant Gliomas (2012)
  • Author(s): Mukasa A
  • Organizer: 9th Meeting of Asian Society for Neuro-Oncology
  • Place of Presentation: Taipei (Taiwan)
  • Invited
• [Presentation] 組織型、悪性度、随伴する遺伝子異常により異なる悪性神経膠腫におけるIDH変異の意義 (2012)
  • Author(s): 武笠晃丈
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌(ロイトン札幌)
• [Presentation] Low grade gliomaの分子診断と治療への応用 (2012)
  • Author(s): 武笠晃丈
  • Organizer: 第70回日本脳神経外科学会総会
  • Place of Presentation: 大阪（大阪国際会議場）
• [Presentation] Low grade gliomaの分子診断と治療への応用 (2012)
  • Author(s): 武笠晃丈
  • Organizer: 第30回日本脳腫瘍学会
  • Place of Presentation: 広島（グランドプリンスホテル広島）
• [Presentation] 悪性グリオーマにおけるIDH遺伝子変異と染色体1p19qLOHおよびp53変異の関連とその意義 (2011)
  • Author(s): 武笠晃丈
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Low grade gliomaの遺伝子変異解析の診断と治療への貢献 (2011)
  • Author(s): 武笠晃丈
  • Organizer: 第69回日本脳神経外科学会総会
  • Place of Presentation: 横浜
• [Presentation] Gene Profiling of Malignant Brain Tumors -The Present Status and Next Step - (2011)
  • Author(s): 武笠晃丈
  • Organizer: 第24回 国際がん研究シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] 悪性神経膠腫における変異型EGF受容体に対する分子標的療法とその治療耐性獲得機構 (2011)
  • Author(s): 武笠晃丈
  • Organizer: 第29回日本脳腫瘍学会
  • Place of Presentation: 岐阜
• [Presentation] Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells (2011)
  • Author(s): Mukasa A
  • Organizer: The 16th Korea -Japan Cancer Research Workshop
  • Place of Presentation: 札幌
• [Presentation] Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells
  • Author(s): Mukasa A
  • Organizer: 19th International Brain Tumor Research and Therapy Conference
  • Place of Presentation: Niagara Falls (Canada)
• [Presentation] がんゲノムプロジェクト進行とともに急拡大する脳腫瘍の遺伝子異常の新知見とその臨床的意義
  • Author(s): 武笠晃丈
  • Organizer: 第18回多摩脳腫瘍研究
  • Place of Presentation: 東京（三鷹産業プラザ）
  • Invited
• [Presentation] 治療戦略立案のために有用な神経膠腫 grade 2/3 の遺伝子診断
  • Author(s): 武笠晃丈
  • Organizer: 第41回 ニューロ・オンコロジィの会
  • Place of Presentation: 東京
  • Invited
• [Presentation] オミックス解析技術が拓く悪性神経膠腫に対する個別化治療の可能性
  • Author(s): 武笠晃丈
  • Organizer: 第7回 脳腫瘍の基礎シンポジウム
  • Place of Presentation: 東京
  • Invited